Exploration of the pathogenic mechanisms of inherited cardiomyopathies caused by cardiac troponin T mutations

心肌肌钙蛋白T突变所致遗传性心肌病发病机制探讨

基本信息

  • 批准号:
    17300129
  • 负责人:
  • 金额:
    $ 9.54万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    2005
  • 资助国家:
    日本
  • 起止时间:
    2005 至 2006
  • 项目状态:
    已结题

项目摘要

We created knock-in mice in which a deletion of three base-pairs coding for K210 in cardiac troponin T (cTnT) found in familial dilated cardiomyopathy (DCM) patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca^<2+> sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca^<2+> transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca^<2+> transient was augmented to compensate for decreased myofilament Ca^<2+> sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure and frequent sudden death recapitulating the phenotypes of DCM patients, indicating that global functional defect of the heart due to decreased myofilament Ca^<2+> sensitivity could not be fully compensated by just increasing the intracellular Ca^<2+> transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca^<2+> sensitivity, had profound effects of preventing cardiac enlargement, heart failure and sudden death. These results verify the hypothesis that Ca^<2+> desensitization of cardiac myofilament is the absolute cause of the pathogenesis of DCM associated with this mutation and strongly suggest that Ca^<2+> sensitizers are beneficial for the treatment of DCM patients affected by sarcomeric regulatory protein mutations.
我们创建了敲入小鼠,将家族性扩张型心肌病(DCM)患者心肌肌钙蛋白T (cTnT)中编码K210的三个碱基对的缺失引入内源性基因。与野生型小鼠相比,突变小鼠的膜渗透心肌纤维对Ca^<2+>的敏感性明显降低。突变小鼠心肌细胞Ca^<2+>瞬变峰值振幅增加,且突变小鼠完整心肌纤维产生的最大等距力与野生型小鼠无显著差异,提示Ca^<2+>瞬变增强以补偿肌丝Ca^<2+>敏感性的降低。然而,突变小鼠出现了明显的心脏增大、心力衰竭和频繁的猝死,再现了DCM患者的表型,这表明心肌纤维Ca^<2+>敏感性降低导致的心脏整体功能缺陷不能仅仅通过增加细胞内Ca^<2+>瞬时值来完全补偿。我们发现一种阳性的肌力药物,匹莫苯丹,能直接增加肌丝Ca^<2+>的敏感性,对预防心脏增大、心力衰竭和猝死有深远的作用。这些结果验证了Ca^<2+>心肌纤丝脱敏是与该突变相关的DCM发病机制的绝对原因的假设,并强烈提示Ca^<2+>增敏剂有益于治疗受肌肉调节蛋白突变影响的DCM患者。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
遺伝子異常から肥大型心筋症形成へのメカニズム
遗传异常导致肥厚型心肌病形成的机制
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kitada K;et al;Kitada K;Du et al.;Sachio Morimoto;Du et al.;森本幸生;Sachio Morimoto;森本 幸生
  • 通讯作者:
    森本 幸生
Functional abnormality of regulatory proteins of sarcomere in idiopathic dilated cardiomyopathy
特发性扩张型心肌病肌节调节蛋白功能异常
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kitada K;et al;Kitada K;Du et al.;Sachio Morimoto;Du et al.;森本幸生;Sachio Morimoto
  • 通讯作者:
    Sachio Morimoto
肥大型心筋症ハンドブック -life long disease としてのマネジメント
肥厚型心肌病手册 - 作为终生疾病的管理
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kitada K;et al;Kitada K;Du et al.;Sachio Morimoto;Du et al.;森本幸生;Sachio Morimoto;森本 幸生;Yumoto et al.;Du et al.;森本幸生;森本幸生
  • 通讯作者:
    森本幸生
肥大型心筋症ハンドブック-life long diseaseとしてのマネジメント
肥厚型心肌病手册 - 作为终生疾病的管理
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kitada K;et al;Kitada K;Du et al.;Sachio Morimoto;Du et al.;森本幸生;Sachio Morimoto;森本 幸生;Yumoto et al.;Du et al.;森本幸生
  • 通讯作者:
    森本幸生
Drastic Ca^<2+> sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy.
在遗传性限制性心肌病中,肌丝的剧烈Ca ^ 2 敏化与肌钙蛋白I的微小结构变化相关。
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MORIMOTO Sachio其他文献

MORIMOTO Sachio的其他文献

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{{ truncateString('MORIMOTO Sachio', 18)}}的其他基金

Pathogenic mechanism of congestive heart failure in a mouse model of dilated cardiomyopathy with brain serotonin dysfunction
扩张型心肌病伴脑血清素功能障碍小鼠模型充血性心力衰竭的发病机制
  • 批准号:
    23300145
  • 财政年份:
    2011
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Exploration of the pathogenic mechanisms of inherited cardiomyopathies caused by cardiac troponin T mutations
心肌肌钙蛋白T突变所致遗传性心肌病发病机制探讨
  • 批准号:
    15300136
  • 财政年份:
    2003
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Functional analyset of mutations in human cardiac troponin T that cause familial hypertrophic cardiomyopathy
导致家族性肥厚型心肌病的人心肌肌钙蛋白T突变的功能分析
  • 批准号:
    11670045
  • 财政年份:
    1999
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanism of pH sensitivity of muscle contraction : investigation using site-directed mutagenesis
肌肉收缩 pH 敏感性的分子机制:利用定点突变进行研究
  • 批准号:
    08680891
  • 财政年份:
    1996
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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